T cell development in the thymus is tightly controlled by complex regulatory mechanisms at multiple checkpoints. Currently, many studies have focused on the transcriptional and posttranslational control of the intrathymic journey of T-cell precursors. However, over the last few years, compelling evidence has highlighted cell metabolism as a critical regulator in this process. Different thymocyte subsets are directed by distinct metabolic pathways and signaling networks to match the specific functional requirements of the stage. Here, we epitomize these metabolic alterations during the development of a T cell and review several recent works that provide insights into equilibrating metabolic quiescence and activation programs. Ultimately, understanding the interplay between cellular metabolism and T cell developmental programs may offer an opportunity to selectively regulate T cell subset functions and to provide potential novel therapeutic approaches to modulate autoimmunity.
Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells and is becoming a serious public health threat. Despite the increasing incidence rate of T1D worldwide, our understanding of why T1D develops and how T cells lose their self-tolerance in this process remain limited. Recent advances in immunometabolism have shown that cellular metabolism plays a fundamental role in shaping T cell responses. T cell activation and proliferation are supported by metabolic reprogramming to meet the increased energy and biomass demand, and deregulation in immune metabolism can lead to autoimmune disorders. Specific metabolic pathways and factors have been investigated to rectify known deficiencies in several autoimmune diseases, including T1D. Most therapeutic strategies have concentrated on aerobic glycolysis to limit T cell responses, whereas glycolysis is the main metabolic pathway for T cell activation and proliferation. The use of metabolic inhibitors, especially glycolysis inhibitors may largely leave T cell function intact but primarily target those autoreactive T cells with hyperactivated metabolism. In this review, we provide an overview of metabolic reprogramming used by T cells, summarize the recent findings of key metabolic pathways and regulators modulating T cell homeostasis, differentiation, and function in the context of T1D, and discuss the opportunities for metabolic intervention to be employed to suppress autoreactive T cells and limit the progression of β-cell destruction.
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